biostudies-literatureRosenberger GU.S. Department of Health & Human Services | NIH | National Cancer InstituteNCI NIH HHSNIH HHSNIGMS NIH HHS3909https://www.ebi.ac.uk/biostudies/studies/S-EPMC11082183biostudies-literatureUnknown15(1)Aberrant signaling pathway activity is a hallmark of tumorigenesis and progression, which has guided targeted inhibitor design for over 30 years. Yet, adaptive resistance mechanisms, induced by rapid, context-specific signaling network rewiring, continue to challenge therapeutic efficacy. Leveraging progress in proteomic technologies and network-based methodologies, we introduce Virtual Enrichment-based Signaling Protein-activity Analysis (VESPA)-an algorithm designed to elucidate mechanisms of cell response and adaptation to drug perturbations-and use it to analyze 7-point phosphoproteomic time series from colorectal cancer cells treated with clinically-relevant inhibitors and control media. Interrogating tumor-specific enzyme/substrate interactions accurately infers kinase and phosphatasNature communicationsNetwork-based elucidation of colon cancer drug resistance mechanisms by phosphoproteomic time-series analysis.PMC11082183R01 GM137031U54 CA209997U54 CA274506S10 OD012351S10 OD032433R35 GM139585U01 CA272610S10 OD021764Kerwin PKaran CRosenberger GHe JGriffin ATTurunen MHonig BLi WLiu YPampou SMurray DCalifano ASubramaniam PSfalseNetwork-based elucidation of colon cancer drug resistance mechanisms by phosphoproteomic time-series analysis.Aberrant signaling pathway activity is a hallmark of tumorigenesis and progression, which has guided targeted inhibitor design for over 30 years. Yet, adaptive resistance mechanisms, induced by rapid, context-specific signaling network rewiring, continue to challenge therapeutic efficacy. Leveraging progress in proteomic technologies and network-based methodologies, we introduce Virtual Enrichment-based Signaling Protein-activity Analysis (VESPA)-an algorithm designed to elucidate mechanisms of cell response and adaptation to drug perturbations-and use it to analyze 7-point phosphoproteomic time series from colorectal cancer cells treated with clinically-relevant inhibitors and control media. Interrogating tumor-specific enzyme/substrate interactions accurately infers kinase and phosphatas2024-01-01T00:00:00Z2024 May2026-07-15T14:04:35.38Z2025-09-01T03:08:12.44ZS-EPMC110821833872449310.1038/s41467-024-47957-3